12 June 2019

A new form of gene therapy for haemophilia has been developed aimed at providing treatment for paediatric patients.

Italian scientists say they have developed viral vectors that can both hide from the immune system and cause sustainable production of clotting factors during growth into adulthood. So far, they have been tested in mice and non-human primates.

Assistant Professor Alessio Cantore and Professor Luigi Naldini, from Vita Salute San Raffaele University in Milan, looked at ways of making virus-based gene therapy for haemophilia more effective.

Current gene therapy for haemophilia is based upon adeno-associated viral vectors delivering clotting factors into cells in the liver. However, the downside to these viral vectors is that they do not stably integrate into the host genome, meaning that in child recipients, as the liver grows the production of clotting factors may reduce. In addition, many adult patients are naturally immunised against adeno-associated viruses. 

So Cantore, Naldini and their team tested an alternative based on lentiviral vectors, which do stably integrate into the host DNA, and which fewer people have natural immunity against. Lentiviral vectors are usually neutralised by phagocytes, but the team found this destruction could be prevented by incorporating the protein CD47 into the surface of the viruses.

These shielded vectors were able to deliver gene therapy without any signs of toxicity, in mice and macaques. The team hopes they will become widely used for haemophilia and other liver diseases.

Dr Cantore said: “Liver-directed gene therapy for haemophilia using adeno-associated viral vectors has shown successful results in adults with haemophilia.

“However, this type of gene therapy cannot be applied to young paediatric patients in its current form, due to the expected decrease in efficacy with adeno-associated viral vectors after growth.”

He added: “HIV-derived lentiviral vectors may address this challenge and complement adeno-associated viral vector in liver gene therapy for haemophilia and possibly other liver metabolic diseases.

“In our recent work, we generated phagocytosis shielded lentiviral vectors by engineering high surface content of the phagocytosis inhibitor CD47 on the lentiviral vector surface (CD47hi LV).

“We show that CD47hi lentiviral vectors are more resistant to phagocytosis, improve gene transfer efficiency to hepatocytes after intravenous administration to mice and nonhuman primates, without signs of toxicity.”

Full details were published recently in the journal Science Translational Medicine. The researchers hope that human trials can begin soon.

Source: Milani, M., Annoni, A., Moalli, F., Liu, T., Cesana, D., Calabria, A., Bartolaccini, S., Biffi, M., Russo, F., Visigalli, I., Raimondi, A., Patarroyo-White, S., Drager, D., Cristofori, P., Ayuso, E., Montini, E., Peters, R., Iannacone, M., Cantore, A., Naldini, L. (2019) “Phagocytosis-shielded lentiviral vectors improve liver gene therapy in non-human primates”, Science Translational Medicine, available from doi: 10.1126/scitranslmed.aav7325


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